This is an application for a K23 award for Dr. Justin Baker, a psychiatrist and neuroscientist at McLean Hospital and the Harvard Medical School. Dr. Baker is establishing himself as a young investigator in patient- oriented clinical research of schizophrenia and bipolar disorder. This K23 award will provide Dr. Baker with the support necessary to accomplish the following goals: (1) to become expert at patient-oriented clinical research in psychotic disorders; (2) to conduct investigations of neurobiological correlates in patients in early stages of psychotic illness; (3) to implement advanced genetic methods in clinical studies; and (4) to develop an independent clinical research career. To achieve these goals, Dr. Baker has assembled a mentoring team comprised of two primary mentors, Dr. Jordan Smoller, Director of Psychiatric Genetics at Massachusetts General Hospital (MGH), who conducts genetic investigations in schizophrenia and bipolar disorder, and Dr. Dost Ongur, Chief of the McLean Hospital Psychotic Disorders Division who leads a neuroimaging laboratory studying the biology of psychotic illness. Consultants include Dr. Randy Buckner, Director of Psychiatric Neuroimaging at MGH, a neuroscientist who contributes advanced neuroimaging expertise, Larry Seidman, a psychologist with expertise in the early phases of schizophrenia and bipolar disorder, and Dr. Ben Neale, an expert in statistics and statistical genetics, particularly in the field of psychiatric genetics. Psychotic disorders, including schizophrenia (SZ and bipolar disorder with psychosis (BPP) are heritable conditions, and yet little is known about changes to brain structure and function that may arise from genetic variation and in turn confer clinical risk. Dr. Baker's research will focus on the neural system changes that accompany elevated genetic risk for SZ and BPP in a psychiatrically healthy young adult population (Aim 1) and the neural system changes that accompany early stages of SZ and BPP (Aim 2). In Aim 1, Dr. Baker will establish the effects of polygenic risk factors for SZ and BPP, obtained from the Psychiatric Genetics Consortium, on brain structure and function, by leveraging a large existing imaging-genetics sample (>1800) from psychiatrically healthy individuals. In addition, he will create a novel polygenic risk score based on variation in brain function in healthy volunteers and test whether this score informs clinical outcomes in a cross-diagnostic patient sample. In Aim 2, Dr. Baker will analyze two data sets of brain MRI from early stages of psychosis: one from an existing sample of structural and functional MRI scans obtained from patients prodromal for psychosis from the North American Prodrome Longitudinal Study; for the second, Dr. Baker will conduct a cross-sectional pilot study to generate preliminary data on the effects of newly diagnosed psychosis on brain structure and function, leveraging the clinical services of the McLean Psychotic Disorders Division. This research will form the basis for a study of risk prediction modeling in high risk and newly diagnosed schizophrenia and bipolar disorder, to be proposed in an R01 grant application before the end of the K award.